Efficacy and safety of nanoparticle mediated placental gene therapy in nonhuman primates

项目摘要 评估妊娠健康和评估可能的分子和遗传因素的改进方法 不良妊娠结局的相关性目前正在研究中。这些知识的价值有限， 然而，没有能力干预有问题的怀孕。显然困难的一步是翻译 了解胎盘治疗，以改善胎儿健康。治疗胎盘内 怀孕的母亲有几个重要的问题。胎盘治疗需要选择性地靶向 胎盘，以避免对母体生理产生不必要的脱靶效应，并确保治疗胎盘 不会对胎儿造成意外的负面影响。长期目标是建立安全、 在非人灵长类动物中进行有效的胎盘特异性基因治疗，以建立潜在的治疗方法 胎儿生长受限和其他胎盘发挥作用的妊娠病理学的策略。 此外，在非人灵长类动物中开发器官特异性靶向方法将允许 在高度可转化为人类的动物模型中开发其他疾病特异性妊娠模型。 本申请的总体目标是评估基于聚合物的纳米颗粒的可行性和安全性 其可以被胎盘合胞体摄取并导致转基因表达，并允许追踪， 靶向开发用于纳米载体的器官特异性递送。这一建议背后的理由是， 预计将朝着特定的，可平移的治疗输送机制迈出重要的一步， 胎盘和扩大疾病建模的能力，在非人类灵长类动物。 这些具有前瞻性和创新性的研究将使佛罗里达大学和威斯康星州大学- 麦迪逊研究人员准备朝着最终目标努力，能够“治疗胎盘”， 短暂的器官对我们的存在至关重要，但极难用治疗方法解决 因此，必须采取有效的干预措施，以改善妊娠结果、妇女健康和终身健康。本研究 也将为在非人灵长类动物中开发其他器官特异性疾病模型开辟可能性。

Project Summary Improved methods for assessing pregnancy well-being, and assessing possible molecular and genetic correlates of poor pregnancy outcomes are currently in development. This knowledge is of limited value, however, without the ability to intervene in troubled pregnancies. The obvious difficult step is to translate knowledge to be gained into placental therapeutics to improve fetal health. Treating the placenta within the pregnant mother has several significant concerns. Placental therapeutics will need to selectively target the placenta to avoid unwanted off-target effects on maternal physiology and to ensure that treating the placenta does not result in inadvertent negative consequences for the fetus. The long-term goal is to establish safe, efficacious and placenta-specific gene therapy in a nonhuman primate in order to establish potential treatment strategies for fetal growth restriction and other pregnancy pathologies in which the placenta plays a role. Furthermore, the development of an organ-specific targeting approach in a nonhuman primate will allow the development of other disease-specific models of pregnancy in an animal model highly translatable to human. The overall objective of this application is to assess the feasibility and safety of a polymer-based nanoparticle that can be taken up by the placental syncytium and result in transgene expression and allow tracking and targeting developments for organ-specific delivery of nanocarriers. The rationale behind this proposal is that it is expected to make significant steps toward a specific, translatable delivery mechanism for therapy in the placenta and to broaden the capabilities of disease modelling in the nonhuman primate. These forward-looking and innovative studies will position University of Florida and University of Wisconsin- Madison investigators to be poised to work towards the ultimate goal, to be able to “treat the placenta”, an ephemeral organ fundamental to our existence, yet exceedingly difficult to address with therapeutic intervention, in the interest of improving pregnancy outcomes, women’s health and lifelong health. This study will also open possibilities for other organ-specific disease models to be developed in the nonhuman primate.